Hydrogel-forming sustained-release preparation

ABSTRACT

The invention provides a hydrogel-type sustained-release preparation comprising (1) at least one drug, (2) an additive which insures a penetration of water into the core of the preparation and (3) a hydrogel-forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract such as stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon. 
     By the preparation of the invention, the drug is efficiently released and absorbed even in the colon so that a steady and sustained release effect can be achieved.

TECHNICAL FIELD

The present invention relates to a sustained-release preparation capableof releasing a drug for a prolonged period of time. More particularly,the invention relates to a hydrogel-type sustained-release preparationcapable of satisfactorily releasing a drug not only in the upperdigestive tract but also in the lower digestive tract, particularly inthe colon.

BACKGROUND ART

A variety of hydrogel-type preparations have heretofore been proposedfor realizing sustained release of drugs. For example, JP-A-62-120315discloses a preparation obtained by compression-molding a drug, ahydrogel-forming water-soluble polymer and an enteric coating base (theterm “JP-A”as used herein means an “unexamined published Japanese patentapplication”). JP-A-63-215620 discloses a hydrogel-type preparationwhich comprises a core comprising a drug and a water-soluble polymer andan outer layer comprising a water-soluble polymer as a base.JP-B-40-2053 discloses a sustained-release preparation comprising amixture of a drug and a high polymer of ethylene oxide and, as anoptional component, a hydrophilic substance (the term “JP-B” as usedherein means an “examined Japanese patent publication”).

However, all of these preparations are designed to release a drugcontinuously while the administered preparation is still retained in theupper digestive tract, typically in the stomach and small intestine, andare not intended to provide for a release of the drug in the lowerdigestive tract, typically in the colon, where little water isavailable. Thus, for any sustained-release preparation designed torelease a drug for absorption during its descent down in the digestivetract, the extent of drug release and absorption in the upper digestivetract has a major influence on the bioavailability of the drug. However,it is generally believed that the release of the drug in the colon canhardly be expected because of the paucity of water and the influence ofspodogenous contents etc. and actually, little research has beenundertaken on drug release in the colon (Pharm. Tech. Japan 8 (1),(1992), 41).

Furthermore, the biological half-life of a drug per se is also animportant factor in the design of sustained-release preparations. It hasbeen generally considered difficult to design a preparation providingfor dramatic sustained release for a drug having a short half-lifeperiod (The Pharmaceuticals Monthly 25 (11), (1983), 29).

DISCLOSURE OF INVENTION

As a result of extensive studies on the sustained-release of a drug, theinventors of the present invention discovered that the release of a drugin the colon, which is low in water content, can be achieved byproviding a preparation adapted to absorb water into its core to undergosubstantially complete gelation during its stay in the upper digestivetract such as the stomach and small intestine, and then move in the formof the gel down to the lower digestive tract. The present invention wasachieved based on the above finding.

Thus, the present invention relates to a hydrogel-type sustained-releasepreparation comprising (1) at least one drug, (2) an additive providingfor a penetration of water into the core of the preparation, and (3) ahydrogel-forming polymer, which preparation undergoes a substantiallycomplete gelation during its stay in the upper digestive tract such asthe stomach and small intestine and is capable of releasing a drug inthe colon.

The term “substantially complete gelation” of the preparation as used inthis specification refers to the state in which not less than about 70%,preferably not less than about 80%, of the preparation is gelled.

Since even the colon can be utilized as a site of absorption, thesustained-release preparation of the present invention prolongs theabsorption period of the drug to a remarkable extent and, hence, insuresa steady blood level of the drug. Thus, the preparation of the presentinvention absorbs water during its stay in the upper digestive tract toundergo a substantially complete gelation and then moves down into thelower digestive tract with its surface being constantly eroded, andmaintains drug release by further erosion in the lower digestive tract,with the result that a sustained and sufficient absorption of the drugis achieved even in the colon where little water is available.

The sustained-release preparation of the present invention is describedin further detail hereinafter.

The drug or drugs which can be used in the preparation according to thepresent invention are not particularly limited in kind, provided thatthey are used for sustained-release system.

Thus, representative examples of the drugs include antiinflammatory,antipyretic, anticonvulsant and/or analgesic agents such asindomethacin, diclofenac, diclofenac Na, codeine, ibuprofen,phenylbutazone, oxyphenbutazone, mepirizol, aspirin, ethenzamide,acetaminophen, aminopyrine, phenacetin, scopolamine butylbromide,morphine, etomidoline, pentazocine, fenoprofen calcium, etc;tuberculostats such as isoniazid, ethambutol hydrochloride, etc.;cardiocirculatory system drugs such as isosorbide dinitrate,nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipinehydrochloride, dipyridamole, amrinone, indenolol hydrochloride,hydralazine hydrochloride, methyldopa, furosemide, spironolactone,guanethidine nitrate, reserpine, amosulalol hydrochloride, etc.;antipsychotic agents such as chlorpromazine hydrochloride, amitriptylinehydrochloride, nemonapride, haloperidol, moperone hydrochloride,perphenazine, diazepam, lorazepam, chlordiazepoxide, etc.;antihistaminic agents such as chlorpheniramine maleate, diphenhydraminehydrochloride, etc.; vitamins such as thiamine nitrate, tocopherolacetate, cycothiamine, pyridoxal phosphate, cobamamide, ascorbic acid,nicotinamide, etc.; antigout agents such as allopurinol, colchicine,probenecid, etc.; hypnotic sedatives such as amobarbital,bromovalerylurea, midazolam, chloral hydrate, etc.; antineoplasticagents such as fluorouracil, carmofur, aclarubicin hydrochloride,cyclophosphamide, thiotepa, etc.; anticongestants such asphenylpropanolamine, ephedrine, etc.; antidiabetics such asacetohexamide, insulin, tolbutamide, etc.; diuretics such ashydrochlorothiazide, polythiazide, triamterene, etc.; bronchodilatorssuch as aminophylline, formoterol fumarate, theophylline, etc;antitussives such as codeine phosphate, noscapine, dimemorfan phosphate,dextromethorphan, etc; antiarrhythmic agents such as quinidine nitrate,digitoxin, propafenone hydrochloride, procainamide, etc.; surfaceanesthetics such as ethyl aminobenzoate, lidocaine, dibucainehydrochloride, etc.; antiepileptics such as phenytoin, ethosuximide,primidone, etc.; synthetic adrenocortical steroids such ashydrocortisone, prednisolone, triamcinolone, betamethasone, etc.;digestive system drugs such as famotidine, ranitidine hydrochloride,cimetidine, sucralfate, sulpiride, teprenone, plaunotol, etc.; centralnervous system drugs such as indeloxazine, idebenone, tiapridehydrochloride, bifemeline hydrochloride, calcium hopantenate, etc.;hyperlipemia treating agents such as pravastatin sodium etc.; andantibiotics such as ampicillin phthalidyl hydrochloride, cefotetan,josamycin and so on. A typical drug among the above drugs is nicardipinehydrochloride. Drugs having short biological half-lives can also beutilized. The amount of the drug may be any of pharmaceuticallyeffective amount, but is usually below 85 weight %, and preferably below80 weight % based on the total weight of the preparation.

In order that these drugs may be readily absorbed in the colon which islow in water content, it is preferable to improve their solubilities inadvance. Known techniques for improving the solubility of a drug whichcan be applied to hydrogel preparation can be employed. Among suchtechniques (solubilizing treatment) can be mentioned the methodcomprising adding a surfactant (e.g. polyoxyethylene-hydrogenated castoroils, polyoxy-ethylene-sorbitan higher fatty acid esters,polyoxyethylene polyoxypropylene glycols, sucrose fatty acid esters,etc.) and the method comprising preparing a solid dispersion of the drugand a solubilizer such as a polymer (e.g., a water-soluble polymer suchas hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP),polyethylene glycol (PEG), etc. or an enteric polymer such ascarboxymethylethylcellulose (CMEC), hydroxypropylmethylcellulosephthalate (HPMCP), methyl methacrylate-methacrylic acid copolymer(Eudragit L and S; the trade name of Rhom & Haas Co.), etc.). When thedrug is a basic substance, the method comprising adding an. organic acidsuch as citric acid, tartaric acid or the like can be employed. Ifnecessary, the method involving the formation of a soluble salt or themethod comprising forming a clathrate using cyclodextrin or the like canalso be employed. These procedures for solubilization can be modified asnecessary according to the particular drug.

[“Recent Manufacturing Pharmacy Technique and its Application I”, IsamuUtsumi et al., Medicinal Journal, 157-159 (1983); and “PharmacyMonograph No. 1, Bioavailability”, Tsuneji Nagai et al., SoftscienceCo., 78-82 (1988)]

Among these methods, the method comprising preparing a solid dispersionof the drug and a solubilizer is particularly preferred (cf.JP-A-56-49314 and French Patent 2460667).

The additive for allowing water to penetrate into the core of thepreparation according to the present invention (this additive forinsuring a penetration of water into the preparation core willhereinafter be referred to as “hydrophilic base”) is such that theamount of water required to dissolve 1 g of the hydrophilic base is notmore than 5 ml and preferably not more than 4 ml at the temperature of20±5° C. The higher the solubility of the hydrophilic base in water, themore effective is the base in allowing water into the core of thepreparation. The hydrophilic base includes, inter alia, highlyhydrophilic polymers such as polyethylene glycol (PEG; e.g. PEG400,PEG1500, PEG4000, PEG6000 and PEG20000, produced by Nippon Oils and FatsCo.) and polyvinylpyrrolidone (PVP; e.g. PVP K30, the trade name ofBASF), sugar alcohols such as D-sorbitol, xylitol, etc., sugars such assucrose, anhydrous maltose, D-fructose, dextran (e.g. dextran 40),glucose, etc., surfactants such as polyoxyethylene-hydrogenated castoroil (HCO; e.g. Cremophor RH40 produced by BASF, HCO-40 and HCO-60produced by Nikko Chemicals Co.), polyoxyethylene-polyoxypropyleneglycol (e.g. Pluronic F68 produced by Asahi Denka Kogyo K.K.),polyoxyethylene-sorbitan high molecular fatty acid ester (Tween; e.g.Tween 80 produced by Kanto Kagaku K.K.), etc.; salts such as sodiumchloride, magnesium chloride, etc.; organic acids such as citric acid,tartaric acid, etc.; amino acids such as glycine, β-alanine, lysinehydrochloride, etc.; and amino sugars such as meglumine.

Preferred ones are PEG6000, PVP, D-sorbitol, etc.

The proportion of such hydrophilic base depends on the characteristicsof the drug (solubility, therapeutic efficacy, etc.) and content of thedrug, solubility of the hydrophilic base itself, characteristics of thehydrogel-forming polymer used, the patient's condition at the time ofadministration and other factors. However, the proportion may preferablybe a sufficient level to achieve a substantially complete gelationduring the stay of the preparation in the upper digestive tract. Thepreparation stays in the upper digestive tract in a different perioddepending on the species and the individual but in about 2 hours afteradministration in the case of dogs and in about 4 to 5 hours afteradministration in the case of human (Br. J. clin. Pharmac, (1988) 26,435-443). For administration to human, the proportion may preferably bea sufficient level to achieve a substantially complete gelation in about4 to 5 hours after administration. The proportion of the hydrophilicbase is, therefore, generally about 5-80% by weight and preferably about5-60% by weight based on the total weight of the preparation.

When the content of the hydrophilic base is too small, the necessarygelation into the core of the preparation does not proceed so that therelease of the drug in the colon becomes insufficient. On the otherhand, when the content of the hydrophilic base is excessive, thegelation proceeds in a shorter time but the resulting gel becomes sofragile that the release of the drug is too fast, thus failing to insurea sufficient sustained release. Moreover, because the amount of the baseis large, the product becomes bulky.

The hydrogel-forming polymer mentioned above should have the physicalcharacteristics, inclusive of viscosity in the gelled state, whichpermit the preparation of the present invention to retain its shape moreor less during its travel down to the lower digestive tract, namely thecolon, by withstanding the contractile forces of the digestive tractassociated with the digestion of food.

The hydrogel-forming polymer which can be used in the preparation of thepresent invention is preferably a polymer showing a high viscosity ongelation. For example, a polymer showing a viscosity of not less than1000 cps in 1% aqueous solution (at 25° C.) is particularly preferred.

The properties of the polymer depend on its molecular weight. Thehydrogel-forming polymer which can be used in the present invention ispreferably a substance of comparatively high molecular weight, viz. apolymer having an average molecular weight of not less than 2×10⁶ andmore preferably not less than 4×10⁶.

Among such polymers are polyethylene oxide (PEO) having a molecularweight of not less than 2×10⁶ [e.g., Polyox WSR-303 (average mol. wt.:7×10⁶; viscosity: 7500-10000 cps, 1% in H₂O, 25° C.), Poly WSR Coagulant(average mol. wt.: 5×10⁶; viscosity: 5500-7500 cps, under the samecondition above), Polyox WSR-301 (average mol. wt.: 4×10⁶; viscosity:1650-5500 cps, under the same condition above), Polyox WSR-N-60K(average mol. wt.: 2×10⁶; viscosity: 2000-4000 cps, 2% in H₂O, 25° C.),all of which are trade names of Union Carbide Co.];hydroxypropylmethylcellulose (HPMC) [e.g., Metolose 90SH100000(viscosity: 4100-5600 cps., 1%; in H₂O, 20° C.), Metolose 90SH50000(viscosity: 2900-3900 cps, under the same condition above), Metolose90SH30000 (viscosity: 25000-35000 cps, 2% in H₂O, 20° C.), all of whichare trade names of Shin-Etsu Chemicals Co.]; sodiumcarboxymethylcellulose (CMC-Na) [e.g., Sanlose F-150MC (average mol.wt.: 2×10⁵; viscosity: 1200-1800 cps, 1% in H₂O, 25° C.), SanloseF-1000MC (average mol. wt.: 42×10⁴; viscosity: 8000-12000 cps, under thesame condition above), Sanlose F-300MC (average mol. wt.: 3×10⁵;viscosity: 2500-3000 cps, under the same condition above), all of whichare trade names of Nippon Seishi Co., Ltd.]; hydroxyethylcellulose (HEC)[e.g., HEC Daicel SE850 (average mol. wt.: 148×10⁴; viscosity: 2400-3000cps, 1% in H₂O, 25° C.), HEC Daicel SE900 (average mol. wt.: 156×10⁴;viscosity: 4000-5000 cps, under the same condition above), all of whichare trade names of Daicel Chemical Industries]; carboxyvinyl polymers[e.g., Carbopol 940 (average mol. wt.: ca. 25×10⁵; B.F. GoodrichChemical Co.) and so on.

The preferred is a PEO having an average molecular weight of not lessthan 2×10⁶. Where a continuous release of the drug over a long time, forexample more than 12 hours, is required, a polymer having a highermolecular weight, preferably an average molecular weight of not lessthan 4×10⁶, or a higher viscosity, preferably a viscosity of not lessthan 3000 cps at a concentration of 1% in water at 25° C., ispreferable.

The above hydrogel-forming polymer may be used singly, or two or morekind(s) of the above hydrogel-forning polymers in mixture may be used.Or, the mixture of two or more kinds of any polymers, which mixture hascharacteristics suitable for the present invention, may be suitably usedfor the present invention.

In order to insure a release of the drug in the human colon, it isnecessary that a portion of the preparation having undergone gelationstill remain in the colon even as late as at least 6-8 hours, preferablyat least 12 hours, after administration.

In order to provide a hydrogel-type preparation having such properties,although it depends on the volume of the preparation, the kind ofpolymer and the properties and amount of the drug and of the additivefor insuring a penetration of water into the preparation core, it isgenerally preferable that the preparation contains 10-95 weight %(preferably, 15-90 weight %) of the hydrogel-forming polymer based uponthe preparation weighing less than 600 mg, and one preparation containsnot less than 70 mg per preparation and preferably not less than 100 mgper preparation of the hydrogel-forming polymer. If the amount of thispolymer is less than the above-mentioned level, the preparation will nottolerate erosion in the digestive tract for a sufficiently long time anda sufficient sustained release may not be achieved.

Regarding the types and proportions of the hydrophilic base andhydrogel-forming polymer (the latter is hereinafter referred to ashydrogel-forming base), their usefulness has been established by thefollowing experiments.

Experimental Example Types and Proportions of Hydrophilic Base andHydrogel-Forming Base

(1) The Time Course of Gelation Velocity of the Hydrogel-typeSustained-release Preparation According to the Present Invention

Sample 100 parts by weight of hydrogel-forming base Polyox WSR-303(referred to as POLYOX303 hereinafter) blended with 150 parts by weightof hydrophilic base PEG6000 was mixed in a mortar. The mixed compositionwas compression-molded using an oil press at a compression pressure of 1ton/punch to provide tablets each measuring 8.0 mm in diameter andweighing 200 mg.

Gelation Test

Using The Pharmacopeia of Japan XII (referred to “JP” hereinafter)Disintegration Test Fluid 2, a gelation test was carried out by JPDissolution Test Method 2 (paddle method) at a paddle speed of 25 rpm.Sample tablets were taken out at predetermined intervals, the gel layerwas removed and the diameter (D obs) of the portion not forming a gelwas measured. From this D obs value, the gelation index (G) wascalculated (Table 1, FIG. 1 and Equation 1).

The “gelation index” as used herein represents the percentage of theportion of the tablet which has undergone gelation. The method ofcalculating the gelation index is not particularly limited but thefollowing calculation method may be mentioned as an example.

Thus, the test tablet is moistened for a predetermined time, the volume(or weight) of the portion not forming a gel is then measured and theresult is subtracted from the volume (or weight) of the tablet beforethe beginning of the test.

To be specific, the gel layer of the tablet moistened for apredetermined time is removed, the diameter (or thickness) of theportion not forming a gel is then measured and the gelation index iscalculated by means of Equation 1. The gelation index may also becalculated by means of Equation 2 given hereinafter.

As an alternative which takes advantage of the difference in strengthbetween the gel layer and non-gel portion, the diameter (or thickness)under a predetermined pressure is assumed to be the diameter (orthickness) of the portion not forming a gel and the gelation index iscalculated from Equation 1.

TABLE 1 Results of Gelation Test Testing Time D obs G (h) (mm) (%) 0 8.0± 0.0  0 0.5  6.8 ± 0.03 37.9 ± 0.7 1.0 5.8 ± 0.2 61.1 ± 1.8 2.0  4.0 ±0.05 87.9 ± 0.4 3.0 2.0 ± 0.0 98.4 ± 0.0 4.0 0.0 100 5.0 0.0 100 (n = 3,Mean ± S.E.)

$\underset{\_}{{Equation}\quad 1}$${{Gelation}\quad {Index}\quad \left( {G,\%} \right)} = {\left( {1 - \frac{\left( {D\quad {obs}} \right)^{3}}{\left( {D\quad {ini}} \right)^{3}}} \right) \times 100}$$\begin{matrix}{D\quad {obs}:\quad {{The}\quad {diameter}\quad {of}\quad {the}\quad {portion}\quad {not}\quad {gelled}}} \\{{{after}\quad {initiation}\quad {of}\quad {the}\quad {test}}\quad} \\{D\quad {ini}:\quad {{The}\quad {diameter}\quad {of}\quad {the}\quad {preparation}\quad {before}}} \\{\quad {{initiation}\quad {of}\quad {test}}\quad}\end{matrix}$

Results

The hydrogel tablet containing PEG6000 as a hydrophilic base underwentgelation with its core diameter diminishing progressively at asubstantially constant rate. Two hours after the initiation of the test,the hydrogel tablet substantially went through gelation (not less than80%).

(2) Content of Hydrophilic Base

Samples

One-hundred parts by weight of the hydrogel-forming base POLYOX303blended with a varying proportion, from 0 to 150 parts by weight, of thehydrophilic base PEG6000 was mixed in a mortar and compression-moldedusing an oil press at a compression pressure of 1 ton/punch to providetablets each measuring 8.0 mm in diameter and weighing 200 mg.

Gelation Test

Using JP Disintegration Test Fluid No. 2, the gelation test wasperformed by JP Dissolution Test Method 2 (paddle method) at a paddlespeed of 25 rpm. The tablets were taken out at predetermined intervals,the gel layer was stripped off and the diameter (D obs) of the portionnot forming a gel was measured. From the D obs value, the gelation index(G) was calculated (Table 2 and FIG. 2).

TABLE 2 Results of Gelation Test Blending Ratio G (%) POLYOX303:PEG60002 h 4 h 100:0  29.7 ± 2.9 50.5 ± 1.4 100:5  44.2 ± 5.2 78.0 ± 2.1100:10  52.3 ± 2.5 83.9 ± 0.5 100:15  84.6 ± 0.5 91.2 ± 2.0 100:25  84.6± 0.6 N.T. 100:50  85.2 ± 0.6 N.T. 100:100 87.1 ± 0.2 N.T. 100:150 87.9± 0.4 100.0 ± 0.0  N.T.: Not Tested (n = 3, Mean ± S.E.)

Results

It was found that the inclusion of 15 parts by weight (13.0% of tabletweight) of the hydrophilic base PEG6000 resulted in not less than 80%gelation in 2 hours. It was also found that the inclusion of 10 parts byweight (9.% of tablet weight) of the hydrophilic base PEG6000 resultedin not less than 80% gelation in 4 hours.

(3) Screening of Hydrophilic Bases

Samples

One-hundred parts by weight of the hydrogel-forming base POLYOX303blended with 100 parts by weight of each test hydrophilic base was mixedin a mortar and compression-molded using an oil press at a compressionpressure of 1 ton/punch to provide tablets each measuring 8.0 mm indiameter and weighing 200 mg.

Gelation Test

Using JP Disintegration Test Fluid No. 2, the gelation test wasperformed by JP Dissolution Test Method 2 (paddle method) at a paddlespeed of 25 rpm. The tablets were taken out at 2 hours after initiationof the test and the gel layer was stripped off and the diameter (D obs)of the portion not forming a gel was measured. From the D obs value, thegelation index (G) was calculated (Table 3 and FIG. 3).

TABLE 3 Influence of Solubility of Various Additives on Gelation Index GAdditive Solubility** (%) No additive 29.7 ± 2.9 Lactose 8 ml 24.4 ± 1.9D-Mannitol 6 ml 26.8 ± 1.9 Inositol 6 ml 42.0 ± 1.5 Glycine 4 ml 80.9 ±0.7 PEG20000 4 ml 86.2 ± 0.3 Pluronic F68* 4 ml 95.1 ± 0.4 PVP K30 2 ml82.2 ± 2.5 Dextran 40 2 ml 85.9 ± 1.0 Meglumine 2 ml 93.4 ± 0.8 DextroseAnhydrous 2 ml 94.2 ± 1.5 Lysine-HCl 2 ml 95.1 ± 1.3 β-Alanine 2 ml 99.3± 0.2 PEG6000 1 ml 87.1 ± 0.2 Citric acid 1 ml 93.2 ± 0.3 MaltoseAnhydrous 1 ml 93.7 ± 0.7 Xylitol 1 ml 94.0 ± 1.4 Sucrose 1 ml 94.2 ±1.1 D-Sorbitol 1 ml 97.0 ± 0.4 D-Fructose 1 ml 100*Polyoxyethylene[160]polyoxypropylene[30]glycol (n = 3, Mean ± S.E.)**Volume of water required for dissolving 1 gram measured in accordancewith the method for solubility measurement in JP (25 ± 5° C.)

Results

When D-mannitol and lactose, which require more than 6 ml of water and 8ml of water for dissolution of 1 g, were respectively added, the systemsshowed gelation indices comparable to the index of the system usingPOLYOX303 alone, indicating that these additives are less effective incausing gelation to proceed into the core of the tablet.

It was found that as the hydrophilic base providing for not less than80% gelation in 2 hours, highly soluble bases (which require not morethan 5 ml, preferably not more than 4 ml, of water for dissolution of 1gram) such as glycine, PVP K30, PEG6000 and D-sorbitol are suitable.

(4) Studies on Hydrogel-Forming Base

Using acetaminophen and nicardipine hydrochloride (Pd) as model drugs,the proportion and molecular weight of a hydrogel-forming base which arenecessary for the sustained-release preparation were investigated.

I. Study of Optimum Proportion

The relationship between the proportion of a hydrogel-forming base andthe pattern of dissolution was investigated.

1. Acetaminophen

TABLE 4 Formula (mg) Acetaminophen 50 50 50 50 50 PEG6000 50 50 50 50 50POLYOX303 40 50 100 150 300 Weight (mg) 140 150 200 250 400 Diameter(mm) 6.5 7.0 8.0 8.5 9.5

The components mentioned in Table 4 in the indicated proportions weremixed in a mortar, respectively, and each composition wascompression-molded using an oil press at a compression pressure of 1ton/punch to provide tablets (each containing 50 mg of acetaminophen).

2. Nicardipine Hydrochloride (Pd)

In a mixture of water and methanol (1:9) were dissolved 1 part by weightof Pd, 0.2 part by weight of HCO-60 and 0.4 part by weight ofhydroxypropylmethylcellulose (TC-5E, produced by Shin-Etsu Chemical Co.)and the solution was spray-dried using a spray dryer to provideSpray-dried Product 1.

TABLE 5 Formula (mg) Spray-Dried 128 128 128 128 128 128 128 ProductPEG6000 32 32 32 32 32 32 32 POLYOX303 64 96 120 160 200 240 320 Weight(mg) 224 256 280 320 360 400 460 Diameter (mm) 8.5 8.5 8.5 9.0 9.0 9.510.0

The component materials mentioned in Table 5 in the indicatedproportions were respectively mixed in a mortar ind each composition wascompression-molded using an oil press at a compression pressure of 1ton/punch to provide tablets (each containing 80 mg of Pd).

Dissolution Test

Using JP Disintegration Test Fluid 1 or 2, the dissolution test wascarried out by JP Dissolution Test Method 2 (paddle method) using theacetaminophen and nicardipine hydrochloride (Pd) tablets as models.Sampling was performed at predetermined intervals and the amount of thedrug in each sample was determined by the UV method (FIGS. 4 and 5).

Results

It was found that the rate of dissolution could be controlled by varyingthe proportion of the hydrogel-forming base POLYOX303. It was also foundthat when 50 mg of acetaminophen was used as the principal agent and notless than 100 mg (50% of tablet weight) of POLYOX303 was added, asustained release of the drug lasting for not less than 12 hours wasrealized even under vigorous agitation (paddle speed 200 rpm, pH 6.8).Similarly, when 80 mg of Pd was used as the principal agent, theinclusion of not less than 96 mg (37.5% of tablet weight) of POLYOX303insured a sustained release lasting for not less than 12 hours evenunder vigorous agitation (paddle speed 200 rpm, pH 1.2).

The optimum proportion of the hydrogel-forming base depends on the typesand amounts of the drug and hydrophilic base and the desired dissolutionrate, among other factors, but it was found that the larger was theproportion of the hydrogel-forming base, the greater was the sustainmentof release. It was also found that when a sustained release lasting fornot less than 12 hours is desired, it is necessary to include not lessthan about 70 mg, preferably not less than 100 mg, of thehydrogel-forming base per tablet.

II. Study of Relationship between Molecular Weight of Hydrogel-FormingBase and Duration of Release

1. Acetaminophen

TABLE 6 Formula (Parts by Weight) Acetaminophen 50 PEG6000 50Polyethylene Oxide (PEO) 250

As the polyethylene oxide (PEO), those species having average molecularweights of 9×10⁵, 1×10⁶, 2×10⁶, 4×10⁶, 5×10⁶ and 7×10⁶ were used. Ineach case, the component materials were mixed in a mortar andcompression-molded using an oil press at a compression pressure of 1ton/punch to provide tablets each measuring 9.0 mm in diameter andweighing 350 mg.

2. Nicardipine Hydrochloride (Pd)

In a mixture of water and methanol (1:9) were dissolved 1 part by weightof Pd, 0.4 part by weight of HCO-40 and 0.8 part by weight ofhydroxypropylmethylcellulose (TC-5E, produced by Shin-Etsu Chemical Co.)and the solution was spray-dried using a spray dryer to provideSpray-dried Product 2.

TABLE 7 Tablet Formula (Parts by Weight) Spray-Dried Product 2 178PEG6000 48 Polyethylene Oxide (PEO) 344

As the polyethylene oxide (PEO), those species having average molecularweights of 9×10⁵, 1×10⁶, 2×10⁶, 4×10 ⁶, 5×10⁶ and 7×10⁶ were used. Ineach case, the component materials were mixed in a mortar andcompression-molded using an oil press at a compression pressure of 1ton/punch to provide tablets each measuring 11.0 mm in diameter andweighing 568 mg (containing 80 mg of Pd).

Release Test

The acetaminophen- and nicardipine-containing preparations were testedin the same manner as the dissolution test carried out in I. Study ofthe Optimal Proportion (FIGS. 6 and 7).

Results

The rate of dissolution varied with different average molecular weightsof hydrogel-forming base polyethylene oxide (PEO). When 50 mg ofacetaminophen was used as the principal agent, the use of PEO with anaverage molecular weight of not less than 4×10⁶ resulted in a sustainedrelease lasting for not less than 12 hours under vigorous agitation(paddle speed 200 rpm, pH 6.8).

Similarly, when 80 mg of Pd was used as the principal agent, the use ofPEO with an average molecular weight of not less than 2×10⁶ enabled asustained release lasting for not less than 12 hours.

(5) Verification of In Vivo Gelation

Samples

The hydrogel-forming base (POLYOX303) and the hydrophilic base (PEG6000,PVP K30, or D-sorbitol) in the ratios indicated below were respectivelymixed in a mortar and each mixture was compression-molded using an oilpress at a compression pressure of 1 ton/punch to provide tablets eachmeasuring 8.0 mm in diameter and weighing 200 mg.

POLYOX303:PEG6000=100:10, 25, 50, 100

POLYOX303:PVP K30=100:10, 25, 100

POLYOX303:D-sorbitol=100:10, 25, 100

Autopsy Test in Dogs

Male beagle dogs (Dogs A and B) fasted for about 20 hours wererespectively dosed orally with each test preparation, together with 30ml of water. Two hours later, the animals were anesthetized withpentobarbital Na and, after bleeding, the abdomen was opened. The tabletwas recovered from the digestive tract and the D obs value wasdetermined. From this D obs value, the gelation index (G) was calculated(Table 8).

TABLE 8 Autopsy Test Data in Dogs Sample Administered (POLYOX303Position of Autopsy Data In Vitro Dog 100:) Recovery D obs (mm) G (%) G(%) A PEG6000 10 Colon 6.8 38.6 52.3 PEG6000 25 Colon 2.8 95.7 84.6PEG6000 50 Colon N.D. 100 85.2 PEG6000 100 Colon N.D. 100 87.1 PVP K30100 Colon N.D. 100 82.2 D-Sorbitol 100 Colon N.D. 100 97.0 B PEG6000 10Stomach 3.2 93.6 52.3 PEG6000 25 Stomach 2.9 95.2 84.6 PVP K30 10Stomach 2.5 96.9 — PVP K30 25 Stomach 2.9 95.2 — D-Sorbitol 10 Stomach2.3 97.6 — D-Sorbitol 25 Stomach 2.9 95.2 — N.D.: Not Detected

Results

In Dog A, the tablets had already been transported to the colon by 2hours after administration and the upper digestive tract residence timewas less than 2 hours. In contrast, all the tablets except the onecontaining 10 parts of PEG6000 had already undergone not less than 80%gelation, generally in agreement with in vitro data.

In Dog B, the tablets remained in the stomach at 2 hours afteradministration and all the tablets had undergone more than 80% gelation.

The above results indicated that hydrogel tablets containing ahydrophilic base providing for not less than 80% gelation in vitro (PVPK30, PEG6000 and D-sorbitol) in appropriate amounts are ready to gel dueto penetration of water into the tablet core even in vivo.

If necessary, the preparation of the present invention may includeappropriate other pharmaceutically acceptable additives such as vehicles(e.g., lactose, mannitol, potato starch, wheat starch, rice starch, cornstarch, and crystalline cellulose), binders (e.g.,hydroxylpropylmethylcellulose, hydroxypropylcellulose, methylcellulose,and gum arabic), swelling agents (e.g., carboxymethylcellulose,carboxymethylcellulose calcium, and cross-linking carboxymethylcellulosesodium), lubricants (e.g., stearic acid, calcium stearate, magnesiumstearate, talc, magnesium meta-silicate aluminate, calcium hydrogenphosphate, and anhydrous calcium hydrogen phosphate), fluidizers (e.g.,hydrous silica, light anhydrous silicic acid, and dried aluminumhydroxide gel), colorants (e.g., yellow iron sesquioxide and ironsesquioxide), surfactants (e.g., sodium lauryl sulfate, sucrose fattyacid ester), coating agents (e.g., zein, hydroxypropylmethylcellulose,and hydroxypropylcellulose), aromas (e.g., l-menthol, peppermint oil,and fennel oil), preservatives (e.g., sodium sorbate, potassium sorbate,methyl p-benzoate, and ethyl p-benzoate), etc.

The preparation of the present invention is a solid preparation having acertain shape and hydrogel-forming ability, and can be manufactured bythe conventional processes utilized for the production of hydrogelpreparations. Typical processes are the compression tablettingcomprising blending the drug, hydrophilic base and hydrogel-formingpolymer, if necessary with the addition of other additives, andcompression-molding the resulting composition; the capsule compressionfilling; the extrusion molding comprising fusing a mixture and settingthe fused mixture; and the injection molding; etc. Thereafter, anycoating treatment such as sugar coating and film coating may be appliedor filing into capsules may be carried out.

Solubilization, if performed, of the drug for use in the preparation ofthe invention can be carried out prior to the above-describedmanufacturing process. The hydrophilic base according to the presentinvention may double as said solubilizer in the case that solubilizationis carried out. For example, the preparation of the present inventioncan be manufactured by a process comprising blending the drug,previously solubilized using the hydrophilic base and, if necessary, adifferent additive, with the hydrogel-forming polymer and, if necessary,other additives, and compression molding the resulting composition.

If required, the sustained-release preparation of the present inventionmay have a immediate-release portion. For example, the preparation ofthe present invention may be provided with such a immediate-release partby way of coating.

Depending on the intended use, the product of the invention can beprovided in the form of a dry coated tablet. For example, when a highblood concentration at a definite time after administration is desired,the core tablet is manufactured according to a formulation providing forrapid drug release (with an increased amount of the drug, a reducedamount of the hydrogel-forming base, and/or an increased amount of thehydrophilic base) and, then, the outer layer is formed using aformulation providing for retarded release (with a reduced amount of thedrug, an increased amount of the hydrogel-forming base and/or a reducedamount of the hydrophilic base) so that the rate of drug release may beaccelerated after a predetermined time.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of a gelation test with a PEG6000-containinghydrogel-type sustained-release preparation;

FIG. 2 shows the results of a gelation test with preparations varying inPEG6000 content;

FIG. 3 shows the gelation indices of various hydrophilic bases after 2hours;

FIG. 4 shows the relationship between the amount of POLYOX303 and thepattern of release (drug: acetaminophen);

FIG. 5 shows the relationship between the amount of POLYOX303 and thepattern of release (drug: nicardipine hydrochloride);

FIG. 6 shows the relationship between the molecular weight of PEO andthe pattern of release (drug: acetaminophen);

FIG. 7 shows the relationship between the molecular weight of PEO andthe pattern of release (drug: nicardipine hydrochloride);

FIG. 8 shows the results of the dissolution test (paddle method) usingthe tablets according to Example 1 and Comparative Example 1;

FIG. 9 shows the results of the gelation test using the tabletsaccording to Example 1 and Comparative Example 1;

FIG. 10 shows the time courses of plasma drug concentration in dogs forthe tablets according to Example 1 and Comparative Example 1;

FIG. 11 shows a comparison between the dissolution test data and theabsorption pattern determined by the deconvolution method for the tabletaccording to Comparative Example 1;

FIG. 12 shows a comparison between the dissolution test data and theabsorption pattern determined by the deconvolution method for the tabletaccording to Example 1;

FIG. 13 shows the time courses of plasma drug concentration in dogs forthe tablets according to Example 2 and Comparative Example 2;

FIG. 14 shows the results of the dissolution test (paddle method) usingthe tablets according to Example 3 (SR) and Comparative Example 3 (SR);

FIG. 15 shows the time courses of plasma drug concentration in dogs forthe tablets according to Example 3 and Comparative Example 3;

FIG. 16 shows the results of the dissolution test (paddle method) usingthe tablets according to Examples 4 and 5;

FIG. 17 shows the results of the dissolution test (paddle method) usingthe tablets according to Examples 6, 7 and 10;

FIG. 18 shows the results of the dissolution test (paddle method) usingthe tablets according to Example 12 and Comparative Example 4;

FIG. 19 shows the time courses of plasma drug concentration in dogs forthe tablets according to Example 12 and Comparative Example 4.

BEST MODE FOR WORKING THE INVENTION

The following examples are intended to describe the preparation of thepresent invention in further detail and should by no means beinterpreted as limiting the scope of the invention.

EXAMPLE 1

AAP 100 (Parts by weight) PEG6000 400 POLYOX303 300

Acetaminophen (AAP) and PEG6000 were melted at 80° C., then cooled tosolidify, and pulverized. The pulverizate and POLYOX303 were mixed in amortar and the resulting composition was compression-molded using an oilpress at a compression pressure of 1 ton/punch to provide tablets eachmeasuring 9 mm in diameter and weighing 400 mg (AAP content: 50 mg).

Comparative Example 1

AAP 100 (Parts by weight) POLYOX303 200

AAP and POLYOX303 were mixed in a mortar and the resulting mixture wascompression-molded using an oil press at a compression pressure of 1ton/punch to provide tablets each measuring 8.5 mm in diameter andweighing 300 mg (AAP content: 100 mg).

Using the tablets according to Example 1 and Comparative Example 1, thefollowing tests were carried out.

(1) Dissolution Test 1

Using JP Disintegration Test Fluid 2, a dissolution test was carried outby JP Dissolution Test Method 2 (paddle method). Sampling was carriedout at predetermined intervals and AAP in each sample solution wasassayed by the UV method (Table 9 and FIG. 8).

TABLE 9 Results of In Vitro Dissolution Test (%) (JP Test Fluid 2,Paddle Method, 200 rpm) Time (h) 0.0 0.5  1.0 2.0  3.0 4.0  6.0 8.0 10.012.0 Comparative 0.0 9.4 15.7 25.8 34.7 42.8 56.5 68.3 78.4 86.4 Example1 Example 1 0.0 8.8 13.2 21.8 32.4 39.1 55.3 69.2 81.9 92.1

(2) Gelation Test

Using JP Disintegration Test Fluid 2, a gelation test was carried out byJP Dissolution Test Method 2 (paddle method) at a paddle speed of 25rpm. The tablets were taken out at predetermined intervals and thediameter (D obs) of the portion not forming a gel was measured, From theD obs values thus found, the gelation index (G) was calculated (Table 10and FIG. 9)

TABLE 10 Results of Gelation Test Testing Time D obs G Preparation (h)(mm) (%) Comparative 0 8.5 — Example 1 2 7.8 ± 0.2 21.5 ± 7.6 4 7.5 ±0.1 30.0 ± 2.5 6 6.7 ± 0.1 50.4 ± 3.0 Example 1 0 9.0 — 2  5.6 ± 0.0376.2 ± 0.3 4  3.1 ± 0.01 96.0 ± 0.1 6   0 ± 0.00 100.0 ± 0   (n = 3,Mean ± S.E.)

(3) Dosing Test in Dogs 1

Male beagle dogs (n=4) fasted for about 20 hours were dosed orally withthe preparation of Example 1×2 tablets (AAP: 100 mg) or the preparationof Comparative Example 1 (AAP: 100 mg), together with 30 ml of water.Blood sampling was carried out at predetermined intervals and the plasmaconcentration of the drug was determined by the HPLC/UV method (Table 11and FIG. 10), the absorption rate was calculated by the deconvolutionmethod using the plasma concentration data generated by intravenousadministration of 100 mg of AAP in water as the weighing function. Theabsorption rate at 24 hours after administration of the preparation ofExample was taken as 100 (Table 12).

TABLE 11 Pharmacokinetic Parameters AUC 0-24 C max T max MRT Preparation(ng · h/ml) (ng/ml) (h) (h) Comparative 1469.7 ± 537.5 343.7 ± 21.7 1.3± 0.3 4.0 ± 1.2 Example 1 Example 1 2702.8 ± 151.5 349.9 ± 36.1 1.5 ±0.3 7.0 ± 0.3 (n = 4, Mean ± S.E.)

TABLE 12 Absorption Rate (%) after Oral Administration of Tablet to DogsTime (h) 0.0 0.5 1.0 2.0 3.0 4.0 6.0 8.0 10.0 12.0 24.0 Comparative 0.08.1 18.7 27.2 33.3 37.8 45.9 50.3 53.1 55.4 58.8 Example 1 Example 1 0.07.5 14.3 31.0 39.1 45.9 60.2 75.5 87.4 95.6 100.0

Results

In the in vitro dissolution test, Comparative Example 1 and Example 1were almost identical in the pattern of dissolution (FIG. 8 and Table 9)but were markedly different from each other in water penetration rate(gelation index) (FIG. 9 and Table 10). When these preparations wereadministered orally to dogs, the plasma drug concentration afteradministration of the preparation of Example 1 was definitely wellsustained as compared with the preparation of Comparative Example 1(FIG. 10). Moreover, both the area under the plasma concentration-timecurve (AUC) and the mean residence time (MRT) of the preparation ofComparative Example 1 were fairly divergent, presumably because ofindividual difference in transport rate in the digestive tract (Table11). In contrast, both the AUC and MRT of the preparation of Example 1were not much varying, suggesting that this preparation was sparinglyinfluenced by the transport rate in the digestive tract. The absorptiontime was also extended, with the result that despite the substantialparity of maximum plasma concentration (C max) between the preparationof Example 1 and that of Comparative Example 1, the AUC afteradministration of the preparation of Example 1 was approximately 1.8times as large.

The absorption pattern determined by the deconvolution method wascompared with the corresponding dissolution test data. In the case ofthe preparation of Comparative Example 1, the absorption of the drugduring the first 2 hours after administration, when the administered,preparation was still in the upper digestive tract, was comparable tothe in vitro dissolution data. However, the absorption after 2 hours wasconsiderably decreased (FIG. 11 and Table 12). The upper digestive tractresidence time of the preparation in fasted dogs is about 2 hours and itis, therefore, clear that the drug was not well released and absorbed inthe lower digestive tract. In contrast, after administration of thepreparation of Example 1, the pattern of absorption was comparable tothe in vitro dissolution data. It is, therefore, evident that the drugwas released and absorbed in the lower digestive tract as efficiently asin the upper digestive tract (FIG. 12 and Table 12).

(4) Autopsy Test in Dogs

Three male beagle dogs fasted for about 20 hours were used. Two, 4 and 6hours before autopsy, each test preparation was administered orallytogether with 30 ml of water. In autopsy, the animals were bled to deathunder pentobarbital Na anesthesia, the abdomen was opened, and thelocation of the preparation in the digestive tract was determined (Table13). The small intestine was divided into 5 segments, which weredesignated as Small Int. 1, 2, 3, 4 and 5, reckoning from the uppermostsegment.

Results

TABLE 13 Location in Digestive Tract Dog No. 2 Hr 4 Hr 6 Hr Comparative1 Colon Colon Colon Example 1 2 Stomach Colon Colon 3 Small Int. 5 ColonColon Example 1 1 Colon Colon Colon 2 Stomach Colon Colon 3 Small Int. 5Colon Colon

It is clear that the preparation of Comparative Example 1, which had alow gelation index, and the preparation of Example 1, the gelation indexof which had been increased by the addition of hydrophilic base, weresubstantially identical in the in vivo transport rate in digestivetract. At 2 hours after administration, both preparations were still inthe stomach in one dog each but were already in Small Int. 5 and colonin the remaining dogs. It was, thus confirmed that the upper digestivetract residence time of the preparation was approximately 2 hours infasted dogs in agreement with the findings heretofore reported. However,the high blood concentration after 2 hours following administration ofthe preparation of Example 1 indicated that the drug was releasedefficiently from this preparation and absorbed notwithstanding the factthat the preparation was present in the lower digestive tract.

EXAMPLE 2

Pd 160 (Parts by weight) HCO-60 80 TC-5E 160 PEG6000 400 POLYOX303 240

Nicardipine hydrochloride (Pd), HCO-60, TC-5E and PEG6000 were dissolvedin a solvent mixture (dichloromethane-methanol) and the solution wasspray-dried using a spray dryer. This dry preparation was mixed withPOLYOX303 in a mortar and the resulting composition wascompression-molded using an oil press at a compression pressure of 1ton/punch to provide tablets each measuring 9.0 mm in diameter andweighing 346.7 mg (Pd content: 53.3 mg).

Comparative Example 2

Pd 130 (Parts by weight) Tween 80 26 Sustained-Release (SR) ComponentCMEC 130 POLYOX303 57.2 Pd 30 Immediate-Release (QR) Component TC-5E 15

In a solvent mixture (dichloromethane-methanol) were dissolvednicardipine hydrochloride (Pd), Tween 80 and CM,EC and the solution wasspray-dried using a spray dryer. The dried mixture was blended withPOLYOX303 and the resulting composition was compression-molded using anoil press at a compression pressure of 0.8 ton/punch to provide tablets(SR) each measuring 8.0 mm in diameter and weighing 171.6 mg (Pdcontent: 65 mg). Separately, Pd and TC-5E were dissolved in a solventmixture (dichloromethane-methanol) and using a Hi-Coater, thisimmediate-release component (QR; Pd: 15 mg) was coated on the SR (Pd: 65mg) component to provide tablets of Comparative Example 2 each weighing194.1 mg (Pd: 80 mg).

Using the tablets of Example 2 and Comparative Example 2, the followingtests were carried out.

(1) Dissolution Test

Using JP Disintegration Test Fluid 1, a dissolution test was carried outby JP Dissolution Test Method 2 (paddle method) at a paddle speed of 200rpm. Sampling was carried out at predetermined intervals and the Pd ineach sample solution was determined by the UV method (Table 14).

TABLE 14 Results of Dissolution Test Time (h)  1.0 2.0  3.0 4.0  5.0 6.0 8.0 10.0 12.0 Comparative 11.9 29.4 46.4 61.9 74.4 82.1 92.1 97.7 100.0Example 2 (SR) Example 2 14.0 28.7 45.1 60.5 73.1 82.2 94.3 99.8 99.3

(2) Gelation Test

Using JP Disintegration Test Fluid 1, a gelation test was carried out byJP Dissolution Test Method 2 (paddle method) at a paddle speed of 25rpm. After a testing time of 2 hours, the tablets were taken out and thediameter (D obs) of the portion not forming a gel was measured. From theD obs value thus found, the gelation index (G) was calculated (Table15).

TABLE 15 Results of Gelation Test Testing Time D obs G Preparation (h)(mm) (%) Comparative 0 8.0 — Example 2 (SR) 2 Unchanged 0 Example 2 09.0 — 2 5.4 ± 0.02 76.2 ± 0.3 (n = 3, Mean ± S.E.)

(3) Dosage Test in Dogs

Male beagle dogs (n=6) fasted for about 20 hours were orally dosed withthe preparation of Example 2×3 tablets, (Pd: 160 mg) or the preparationof Comparative Example 2×2 tablets (Pd: 160 mg), together with 30 ml ofwater. Blood sampling was performed at predetermined intervals and theplasma concentration of the drug was determined by the HPLC/UV method(Table 16 and FIG. 13).

TABLE 16 Pharmacokinetic Parameters AUC C max T max Preparation (ng ·h/ml) (ng/ml) (h) Example 2 375.7 ± 89.3 52.9 ± 15.5 7.3 ± 3.5 (Pd: 160mg) Comparative 125.0 ± 31.8 53.6 ± 12.5 1.3 ± 0.2 Example 2 (Pd: 160mg) (n = 6, Mean ± S.E.)

Results

In the in vitro dissolution test, the preparation of Comparative Example2 (SR) and that of Example 2 were substantially identical in the patternof dissolution (Table 14) but differed from each other significantly inthe rate of water penetration (gelation index) (Table 15). When thesepreparations were orally administered to dogs, the preparation ofExample 2 showed a definitely sustained plasma drug concentration ascompared with the preparation of Comparative Example 2. With respect tothe preparation of Comparative Example 2, the plasma concentration ofthe drug decreased significantly after 2 hours when the administeredpreparation entered into the lower digestive tract, indicating that thedrug was hardly released or absorbed in the lower digestive tract. Incontrast, in the case that the preparation of Example 2 wasadministered, the plasma concentration was well maintained even after 2hours when the preparation was moved into the lower digestive tract,indicating that the drug was effectively released and absorbed in thelower digestive tract. Furthermore, although the preparation of Example2 showed a C max value comparable to that following administration ofthe preparation of Comparative Example 2, the former preparation gave anAUC value approximately 3-fold as large due to the prolonged absorptionperiod.

EXAMPLE 3

Example 3 Pd 65 (Parts by Sustained-Release (SR) Component weight) Tween80 13 CMEC 65 PEG6000 65 POLYOX303 65 Pd 15 Immediate-Release (QR)Component

Nicardipine hydrochloride (Pd), Tween 80 and CMEC were dissolved in asolvent mixture (dichloromethane-methanol) and the solution wasspray-dried using a spray dryer. The dried mixture was blended withPEG6000 and POLYOX303 and the resulting composition wascompression-molded using an oil press at a compression pressure of 1.0ton/punch to provide tablets (SR) each measuring 8.5 mm in diameter andweighing 273 mg (QR; Pd content: 65 mg). For use as theimmediate-release (QR) component, tablets each containing 15 mg of Pdwere separately prepared.

Comparative Example 3

Comparative Example 3 Pd 65 (Parts by Sustained-Release (SR) Componentweight) Tween 80 13 CMEC 65 POLYOX303 28.6 Pd 15 Immediate-Release (QR)Component TC-5E 7.5

Nicardipine hydrochloride (Pd), Tween 80 and CMEC were dissolved in asolvent mixture (dichloromethane-methanol) and the solution wasspray-dried using a spray dryer. The dried mixture was blended withPOLYOX303 and the resulting composition was compression-molded using anoil press at a compression pressure of 0.8 ton/punch to provide tablets(SR) each measuring 8.0 mm in diameter and weighing 171.6 mg (Pdcontent: 65 mg). Separately, Pd and TC-5E were dissolved in a solventmixture (dichloromethane-methanol) and using a Hi-Coater, thisimmediate-release component (QR; Pd content: 15 mg) was coated on the SRcomponent (Pd content: 65 mg) to provide tablets each weighing 194.1 mg(Pd: 80 mg).

(1) Dissolution Test

Using JP Disintegration Test Fluid 2, a dissolution test was carried outby JP Dissolution Test Method 2 (paddle method) at a paddle speed of 200rpm. Sampling was carried out at predetermined intervals and Pd in eachsample solution was assayed by the UV method.

The results of the above dissolution test using the preparation ofComparative Example 3 (SR) and that of Example 3 (SR) are shown in FIG.14.

(2) Gelation Test

Using JP Disintegration Test Fluid 1, a dissolution test was carried outby JP Dissolution Test Method 2 (paddle method) at a paddle speed of 25rpm. After 2 hours, the tablets were taken out, the gel layer wasremoved and the weight (W obs) of the portion not forming a gel wasdetermined. From the W obs value, the gelation index (G) was calculatedby means of Equation 2 given below (Table 17).

TABLE 17 Results of Gelation Test (n = 3, Mean ± S.E.) Testing Time Wobs G Preparation (h) (g) (%) Comparative 0 0.167 — Example 3 (SR) 20.153 ± 0.0 8.2 ± 1.4 Example 3 0 0.276 — (SR) 2 0.055 ± 0.4 79.6 ± 0.4

$\underset{\_}{{Equation}\quad 2}$${G(\%)} = \left( {1 - {\frac{\left( {W\quad {obs}} \right)}{\left( {W\quad {ini}} \right)} \times 100}} \right.$$\begin{matrix}{W\quad {obs}:\quad {{The}\quad {residual}\quad {weight}\quad {after}\quad {removal}\quad {of}\quad {the}}} \\{{{gel}\quad {layer}\quad {after}\quad {initiation}\quad {of}\quad {test}}\quad}\end{matrix}$ $\begin{matrix}{W\quad {ini}:\quad {{The}\quad {weight}\quad {of}\quad {the}\quad {tablet}\quad {before}\quad {initiation}}} \\{\quad {{of}\quad {test}}\quad}\end{matrix}$

(3) Dosage Test in Dogs

Male beagle dogs (n =6) fasted for about 20 hours were orally dosed withtwo tablets each of the preparation of Example 3 SR and QR (Pd: 160 mg)or 2 tablets of the preparation of Comparative Example 3 (Pd: 160 mg),together with 30 ml of water. Blood sampling was performed atpredetermined intervals and the plasma concentration of the drug wasdetermined by the HPLC/UV method (FIG. 15 and Table 18).

TABLE 18 Pharmacokinetic Parameters (n = 6, Mean ± S.E.) AUC 0-24 C maxT max MRT Preparation (ng · h/ml) (ng/ml) (h) (h) Comparative 125.0 ±31.8 53.6 ± 12.5 1.3 ± 0.2 2.4 ± 0.4 Example 3 Example 3 547.1 ± 180.481.6 ± 14.8 3.9 ± 1.1 6.3 ± 1.0

(4) Autopsy Test in Dogs

Three male beagle dogs fasted for about 20 hours were used. Two, 4 and 6hours before autopsy, each test preparation was administered orallytogether with 30 ml of water. In autopsy, the animals were bled to deathunder pentobarbital Na anesthesia, the abdomen was opened, and thelocation of the tablet in the digestive tract was determined (Table 19).The small intestine was divided into 5 segments, which were designatedas Small Int. 1, 2, 3, 4 and 5, reckoning from the uppermost segment.

TABLE 19 Location in Digestive Tract (Small Intestine was Divided into 5Segments) Dog No. 2 Hr 4 Hr 6 Hr Comparative 4 Colon Colon Colon Example3 5 Colon Colon Colon 6 Small Int. 1 Colon Colon Example 3 4 Small Int.5 Colon Colon 5 Colon Colon Colon 6 Small Int. 1 Colon Colon

Results

In the in vitro dissolution test, the preparation of Comparative Example3 (SR) and that of Example 3 (SR) were substantially identical in thepattern of dissolution (Table 14) but diddered considerably from eachother in the gelation index (Table 17). Autopsy revealed substantiallythe same transport rate in the digestive tract for the preparation ofExample 3 and that of Comparative Example 3 (Table 19). When theseprepartaions were administered orally to dogs, the time course of plasmadrug concentration after administration of the preparation of Example 3was definitely better sustained as compared with the preparation ofComparative Example 3. With respect to the preparation of ComparativeExample 3, the plasma concentration decreased remarkably after 2 hourswhen the administered preparation was moved into the lower digestivetract, indicating that the drug was hardly released and absorbed in thelower digestive tract. In contrast, with respect to the preparation ofExample 3, the plasma drug concentration was well sustained even after 2hours when the administered preparation was moved into the lowerdigestive tract, indicating that the drug was effectively released andabsorbed even in the lower digestive tract (FIG. 15). Moreover, althoughthe C max after administration of the preparation of Example 3 was notmuch different from that after administration of the preparation ofComparative Example 3, the former preparation gave an AUC value about4.4 times as large due to the prolonged absorption period (Table 18).

EXAMPLE 4

Example 4 Pd 80 (mg) PVP K30 32 HCO-60 16 POLYOX303 240 Lubricant 4

Nicardipine hydrochloride (Pd), PVP K30 and HCO-60 were dissolved inmethanol. Using a fluidized-bed granulator, this solution was sprayedover POLYOX303 to provide granules. To the granules was added thelubricant and the resulting composition was mixed and thencompression-molded to provide tablets each measuring 9.5 mm in diameterand weighing 372 mg (Pd content: 80 mg).

EXAMPLE 5

Example 5 Pd 80 (mg) TC-5E 32 HCO-60 16 PEG6000 32 POLYOX303 240Lubricant 8 Fluidizer 4

Nicardipine hydrochloride (Pd), TC-5E and HCO-60 were dissolved inwater-methanol (1:9) and the solution was spray-dried. To the driedmixture were added POLYOX303 and 4 mg equivalent of lubricant and themixture was dry-granulated. To the granules were added 4 mg equivalentof lubricant as well as fluidizer and the resulting composition wasmixed and compression-molded to provide tablets each measuring 9.5 mm indiameter and weighing 412 mg (Pd content: 80 mg).

EXAMPLE 6

Example 6 Pd 80 (mg) TC-5E 32 HCO-60 32 PEG6000 32 POLYOX303 384Lubricant 11.2 Fluidizer 5.6

Nicardipine hydrochloride (Pd), TC-5E, HCO-60 and PEG6000 were dissolvedin water-methanol (1:9) and the solution was spray-dried. To this driedpreparation were added POLYOX303 and 5.6 mg equivalent of lubricant andthe mixture was dry-granulated. To the granules thus prepared were added5.6 mg equivalent of lubricant as well as fluidizer and the resultingcomposition was mixed and compression-molded to provide tablets eachmeasuring 11 mm in diameter and weighing 576.8 mg (Pd content: 80 mg).

EXAMPLE 7

Example 7 Pd 80 (mg) TC-5E 64 Tween 80 32 PEG6000 32 POLYOX303 360Lubricant 11.4 Fluidizer 5.7

Nicardipine hydrochloride (Pd), TC-5E and Tween 80 were dissolved inwater-methanol (1:9) and the solution was spray-dried. To this driedpreparation were added PEG6000, POLYOX303 and 5.7 mg equivalent of thelubricant and the mixture was dry-granulated. To the granules thusprepared were added 5.7 mg of lubricant as well as fluidizer and theresulting composition was mixed and compression-molded to providetablets each measuring 11 mm in diameter and weighing 585.1 mg (Pdcontent: 80 mg).

EXAMPLE 8

Pd and TC-5E were dissolved in water-methanol (1:9) and using aHi-Coater, the immediate-release component (Pd: 20 mg) was coated on thetablets of Example 7 (Pd: 80 mg) to provide tablets each weighing 625.1mg (Pd: 100 mg).

EXAMPLE 9

Pd and HPC-SL were dissolved in methanol and using a Hi-Coater, theimmediate-release component (Pd: 20 mg) was coated on the tablets ofExample 7 (Pd: 80 mg) to provide tablets each weighing 625.1 mg (Pd: 100mg).

EXAMPLE 10

Example 10 Pd 80 (mg) TC-5E 64 HCO-40 32 PEG6000 48 POLYOX303 344Lubricant 11.4 Fluidizer 5.7

Pd, TC-5E and HCO-40 were dissolved in water-methanol (1:9) and thesolution was spray-dried. To this dried preparation were added PEG6000,POLYOX303 and 5.7 mg equivalent of lubricant and the mixture wasdry-granulated. To the granules thus prepared were added 5.7 mgequivalent of lubricant as well as fluidizer and the resultingcomposition was mixed and compression-molded to provide tablets eachmeasuring 11 mm in diameter and weighing 585.1 mg (Pd content: 80 mg).

EXAMPLE 11

Example 11 Pd 100 (mg) TC-5E 80 HCO-40 40 PEG6000 48 POLYOX303 300Lubricant 11.4 Fluidizer 5.7

Pd, TC-5E and HCO-40 were dissolved in water-methanol (1:9) and thesolution was spray-dried. To this dried preparation were added PEG6000,POLYOX303 and 5.7 mg equivalent of lubricant and the mixture wasdry-granulated. To the granules were added 5.7 mg equivalent oflubricant as well as fluidizer and the resulting composition was mixedand compression-molded to provide tablets each measuring 11 mm indiameter and weighing 585.1 mg (Pd content: 100 mg).

(1) Dissolution Test

Using JP Disintegration Test Fluid 1, a dissolution test was carried outby JP Dissolution Test Method 2 (paddle method) at a paddle speed of 200rpm. Sampling was carried out at predetermined intervals and Pd in eachsample solution was assayed by the UV method.

The results of dissolution tests for preparations of Examples 4 and 5are shown in FIG. 16.

The results of dissolution tests for preparations of Example 6, Example7 and Example 10 are shown in FIG. 17.

(2) Dosage Test in Dogs

Male beagle dogs (n=6) were orally dosed with 2 tablets of thepreparation of Example 5 or 2 tablets of the preparation of Example 6once a day for 4 consecutive days. Blood sampling was carried out atpredetermined intervals and the plasma concentration of the drug wasdetermined by the HPLC/UV method.

Results

Both of the preparations of Examples 5 and 6, in a once-a-dayadministration, showed high C₂₄ hr values (blood concentrations at 24hours after administration) and high bioavailabilities.

EXAMPLE 12

Example 12 DF 37.5 (mg) PEG6000 37.5 POLYOX303 75.0

Diclofenac Na (DF), PEG6000 and POLYOX303 were mixed in a mortar andusing an oil press the composition was compression-molded at acompression pressure of 1 ton/punch to provide tables measuring 7 mm indiameter and weighing 150 mg (DF: 37.5 mg).

Comparative Example 4

Comparative Example 4 DF 37.5 (mg) POLYOX303 75.0

DF and POLYOX303 were mixed in a mortar and using an oil press themixture was compression-molded at a compression pressure of 1 ton/punchto provide tablets each measuring 6.0 mm in diameter and weighing 112.5mg (DF content: 37.5 mg).

(1) Dissolution Test

Using JP Disintegration Test Fluid 2, a dissolution test was carried outby JP Dissolution Test Method 2 (paddle method). Sampling was carriedout at predetermined intervals and DF in each sample solution wasassayed by the UV method (FIG. 18).

(2) Gelation Test

Using JP Disintegration Test Fluid 2, a gelation test was carried out byJP Dissolution Test Method 2 (paddle method) at a paddle speed of 25rpm. The tablets were taken out at 2 hours intervals and the diameter (Dobs) of the portion not forming a gel was measured. From the D obs valuethus found, the gelation index (G) was calculated (Table 20).

TABLE 20 Results of Gelation Test (n = 3, Mean ± S.E.) Testing Time GPreparation (h) (%) Example 12 2 88.2 ± 1.1 Comparative 2 37.0 ± 4.6Example 4

(3) Dosage Test in Dogs

Male beagle dogs (n=5) fasted for about 20 hours were orally dosed withthe preparation of Example 12 (DF: 37.5 mg) or the preparation ofComparative Example 4 (DF: 37.5 mg), together with 30 ml of water. Bloodsampling was carried out at predetermined intervals and the plasmaconcentration of the drug was determined by the HPLC/UV method (Table 21and FIG. 19).

TABLE 21 Oral Dosage Test (in Fasting Condition) AUC 0-12 C max T maxPreparation (ng · h/ml) (ng/ml) (h) Comparative 5052 ± 1357 1188 ± 1471.7 ± 0.6 Example 4 Example 12 8537 ± 1941 1381 ± 222 3.0 ± 1.3 (n = 5,Mean ± S.E.)

Results

In the in vitro dissolution test, the preparation of Example 12 and thatof Comparative Example 4 were substantially identical in the pattern ofdissolution (FIG. 18) but differed considerably from each other in therate of water penetration (gelation index) (Table 20). When thesepreparations were administered orally to dogs, the preparation ofExample 12 showed a definitely prolonged blood concentration as comparedwith the preparation of Comparative Example 4 (FIG. 19). Furthermore, incomparison with Comparative Example 4, Example 12 gave an AUC valuewhich was about 1.7 times as large (Table 21). Thus, even for diclofenacNa which is an acidic drug, it was confirmed that the application of thepresent invention resulted in an efficient release and absorption of thedrug in the lower digestive tract as well.

EXAMPLE 13

Example 13 DF 75 (mg) PEG6000 75 POLYOX303 150

Diclofenac Na (DF), PEG6000 and POLYOX303 were mixed in a mortar andusing an oil press the composition was compression-molded at acompression pressure of 1 ton/punch to provide tablets each measuring8.5 mm in diameter and weighing 300 mg (DF content: 75 mg).

EXAMPLE 14

Example 14 DF 75 (mg) PEG6000 75 POLYOX303 300

Diclofenac Na (DF), PEG6000 and POLYOX303 were mixed in a mortar andusing an oil press the composition was compression-molded at acompression pressure of 1 ton/punch to provide tablets each measuring9.5 mm in diameter and weighing 450 mg (DF content: 75 mg).

EXAMPLE 15

Example 15 Famotidine 40 (mg) PEG6000 30 POLYOX303 150 Lubricant 2

Famotidine, PEG6000, POLYOX303 and lubricant were mixed andcompression-molded to provide tablets each measuring 8.0 mm in diameterand weighing 222 mg (famotidine content: 40 mg).

EXAMPLE 16

Example 16 Barnidipine Hydrochloride 15 (mg) TC-5E 30 HCO-40 5 PEG2000040 POLYOX303 207 Lubricant 3

Barnidipine hydrochloride, TC-5E and HCO-40 were dissolved inwater-methanol (1:9). Separately, PEG20000 and POLYOX303 were mixed.Using a fluidized-bed granulator, the latter mixture was sprayed withthe above solution. The granules thus prepared were dried, and afteraddition of lubricant, the composition was compression-molded to providetablets each measuring 9.0 mm in diameter and 300 mg (barnidipine HClcontent: 15 mg).

EXAMPLE 17

Example 17 Amosulalol Hydrochloride 40 (mg) Pluronic F68 40 POLYOX303196 Lubricant 4

Amosulalol hydrochloride, Pluronic F68, POLYOX303 and lubricant weremixed, pulverized and dry-granulated. The granules were thencompression-molded to provide tablets each measuring 8.5 mm in diameterand weighing 280 mg (amosulalol HCl content: 40 mg).

EXAMPLE 18

Example 18 Tamusulosin Hydrochloride 0.2 (mg) D-Sorbitol 17.8 Polyox WSRN-60K 180 Lubricant 2

Tamusulosin hydrochloride, D-sorbitol and PEO (Polyox WSR N-60K) werewet-granulated with ethanol and dried. To this dried granules was addedlubricant and the resulting composition was mixed and thencompression-molded to provide tablets each measuring 8 mm in diameterand weighing 200 mg (tamusulosin HCl content: 0.2 mg).

EXAMPLE 19

Example 19 Indeloxazine Hydrochloride 60 (mg) Sucrose 37 HPMC(90SH30000) 180 Lubricant 3

Indeloxazine hydrochloride, sucrose, HPMC and lubricant were mixed anddry-granulated. The granules were then compression-molded to providetablets each measuring 9 mm in diameter and 280 mg (indeloxazine HClcontent: 60 mg).

EXAMPLE 20

Example 20 Formoterol Fumarate 0.16 (mg) Anhydrous Maltose 47.84Carbopol 940 100 Lubricant 2

Formoterol fumarate, anhydrous maltose, Carbopol 940 and lubricant weremixed and the resulting composition was compression-molded to providetablets each measuring 7 mm in diameter and weighing 150 mg (formoterolfumarate content: 0.2 mg).

EXAMPLE 21

Example 21 AAP 100 (mg) PEG6000 200 PEO (Polyox WSR N-60K) 300

Acetaminophen (AAP), PEG6000 and PEO (Polyox WSR N-60K, mean molecularweight: 200 million) were mixed in a mortar and using an oil press themixture was compression-molded at a pressure of 1 ton/punch to providetablets each measuring 11 mm in diameter and weighing 600 mg (AAPcontent: 100 mg).

Comparative Example 5

Comparative Example 5 AAP 100 (mg) PEO (Polyox WSR N-60K) 300

AAP and PEO (POLYOX WSR N-60K) were mixed in a mortar and using an oilpress the mixture was compression-molded at a pressure of 1 ton/punch toprovide tables each measuring 9 mm in diameter and weighing 400 mg (AAPcontent: 100 mg).

(1) Dissolution Test

Using JP Disintegration Test Fluid 2, a dissolution test was carried outby JP Dissolution Test Method 2 (paddle method) at a paddle speed of 200rpm. Sampling was carried out at predetermined intervals and AAP in eachsample solution was assayed by the UV method.

(2) Gelation Test

Using JP Disintegration Test Fluid 2, a gelation test was carried out byJP Dissolution Test Method 2 (paddle method) at a paddle speed of 25rpm. After 2 hours, the tablets were taken out and the diameter (D obs)of the portion not forming a gel was measured. From the D obs value thusfound, the gelation index (G) was calculated.

(3) Dosage Test in Dogs

Male beagle dogs (n =6) fasted for about 20 hours were orally dosed withthe preparation of Comparative Example 5 (AAP: 100 mg) or thepreparation of Example 20 (AAP: 100 mg), together with 30 ml of water.Blood sampling was carried out at predetermined intervals and the plasmaconcentration of the drug was determined by the HPLC/UV method.

Results

In the in vitro dissolution test, the preparation of Comparative Example5 and that of Example 20 were substantially identical in the pattern ofdissolution but the preparation of Example 20, which contained ahydrophilic base, showed a gelation index greater than that of thepreparation of Comparative Example 5. When these preparations wererespectively administered orally to dogs, the plasma concentration ofthe drug was definitely better sustained in the case of Example 21 ascompared with Comparative Example 5. The maximum plasma concentration (Cmax) of the drug after administration of the preparation of Example 21was substantially equal to that after administration of the preparationof Comparative Example 5 but the former preparation was superior in AUCand MRT. Moreover, after administration of the preparation of Example21, the blood concentration of the drug was sustained at a high level upto 12 hours.

INDUSTRIAL APPLICABILITY

The preparation of the present invention absorbs water to undergosubstantially complete gelation during its stay in the upper digestivetract and moves down into the lower digestive tract undergoing constanterosion and continues to release the drug on further erosion. Therefore,this preparation provides for a favorable sustained release of the drugeven in the colon which is low in water content to insure drug releaselasting for about 6 to 18 hours (about 12 to 24 hours if the release inthe upper digestive tract is taken into account) and, hence, insures asteady drug concentration in the blood.

Since the conventional sustained-release preparations release drugs onlyin the upper digestive tract, the duration of release is about 6 hoursat most and subsequent maintenance of blood concentration is relied onthe biological half-life inherent to the drug. In contrast, with respectto the preparation of the present invention, the duration of drugrelease per se is increased. Accordingly, even when the drug is thathaving a short biological half-life and the sustained release thereofhas heretofore been considered difficult, a sufficient bloodconcentration can be maintained over a time period of more than 12hours.

Thus, the preparation of the present invention is capable of sustainingthe efficacy of the drug and the number of administration can bereduced. Further, the side effect of the drug can be reduced bysuppressing rapid increase of blood concentration of the drug and theconstant blood concentration of the drug can be maintained.

As demonstrated in the examples described above, the present inventionis capable of prolonging the absorption of various types of drugs suchas acetaminophen, which is a neutral drug, nicardipine hydrochloride,which is a basic drug, and diclofenac Na, which is an acidic drug.Therefore, the present invention provides a pharmaceutical technologyhaving a great versatility without depending on physical properties ofdrugs.

What is claimed is:
 1. A method for providing drug-release not only inthe upper digestive tract including stomach and small intestine but alsoin the lower digestive tract including the colon, comprising the stepsof: (A) orally administering a preparation having a gelation index of70% or more, said preparation comprising: (1) a drug, wherein the amountof said drug is not more than 85% by weight based on the totalpreparation, (2) an additive which has a solubility such that the volumeof water required for dissolving 1 gram of said additive is not morethan 5 ml, wherein the amount of said additive is from 5 to 80% byweight based on the total preparation, and (3) a hydrogel-formingpolymer having a viscosity of not less than 1000 cps as measured at 1%concentration in water at 25° C., wherein the amount of saidhydrogel-forming polymer is from 10 to 95% by weight based on the totalpreparation and not less than 70 mg per one preparation; (B)substantially complete gelling of the preparation in the upper digestivetract including stomach and small intestine; (C) through travelling ingel-form to the lower digestive tract, releasing the drug not only inthe upper digestive tract including stomach and small intestine but alsoin the lower digestive tract including the colon.
 2. The method asclaimed in claim 1, wherein said preparation has a gelation index of 80%or more.
 3. The method as claimed in claim 1, wherein said additive hasa solubility such that the volume of water required for dissolving 1gram of said additive is not more than 4 ml.
 4. The method as claimed inclaim 1, wherein the amount of said drug is not more than 80% by weightbased on the total preparation.
 5. The method as claimed in claim 1,wherein the amount of said additive is from 5 to 60% by weight based onthe total preparation.
 6. The method as claimed in claim 1, wherein theamount of said hydrogel-forming polymer is from 10 to 90% by weightbased on the total preparation.
 7. The method as claimed in claim 1,wherein the amount of said drug is not more than 80% by weight based onthe total preparation, the amount of said additive is from 5 to 60% byweight based on the total preparation, and the amount of saidhydrogel-forming polymer is from 10 to 90% by weight based on the totalpreparation.
 8. The method as claimed in claim 1, wherein the amount ofsaid hydrogel-forming polymer is not less than 100 mg per onepreparation.
 9. The method as claimed in claim 1, wherein said drug isnicardipine hydrochloride.
 10. The method as claimed in claim 1, whereinsaid drug is tamusulosin hydrochloride.
 11. The method as claimed inclaim 1, wherein said additive is selected from the group consisting ofa highly hydrophilic polymer, a sugar alcohol, a sugar, a surfactant, asalt, an organic acid, an amino acid and an amino sugar.
 12. The methodas claimed in claim 11, wherein said additive is selected from the groupconsisting of polyethylene glycol, polyvinylpyrrolidone, D-sorbitol,xylitol, sucrose, anhydrous maltose, D-fructose, dextran,polyoxyethylene-hydrogenated castor oil,polyoxyethylene-polyoxypropylene glycol, polyoxyethylene-sorbitan higherfatty acid ester, sodium chloride, magnesium chloride, citric acid,tartaric acid, glycine, β-alanine, lysine hydrochloride and meglumine.13. The method as claimed in claim 12, wherein said additive is selectedfrom the group consisting of polyethylene glycol, polyvinylpyrrolidone,and D-sorbitol.
 14. The method as claimed in claim 1, wherein saidadditive is polyethylene glycol.
 15. The method as claimed in claim 1,wherein said additive is selected from the group consisting ofpolyethylene oxide, hydroxypropylmethylcellulose sodiumcarboxymethylcellulose, hydroxyethylcellulose and carboxyvinyl polymers.16. The method as claimed in claim 15, wherein said hydrogel-formingpolymer is polyethylene oxide.
 17. The method as claimed in claim 1,wherein said additive is polyethylene glycol and said hydrogel-formingpolymer is polyethylene oxide.
 18. The method as claimed in claim 1,wherein drug-release is provided in the upper digestive tract and alsoin the lower digestive tract including the colon.
 19. The method asclaimed in claim 1, wherein said preparation is a tablet.
 20. The methodas claimed in claim 1, wherein said gelation index is defined by theequation (1−(D obs)³/(D ini)³)×100 wherein (D ini) is the diameter ofthe preparation before testing and (D obs) is the diameter of thepreparation not gelled at two hours after beginning the test.
 21. Themethod as claimed in claim 1, wherein said gelation index is defined bythe equation (1−(W obs)/(W ini))×100 wherein (W ini) is the weight ofthe preparation before testing and (W obs) is the weight of thepreparation not gelled at two hours after beginning the test.
 22. Amethod for providing drug-release not only in the upper digestive tractincluding stomach and small intestine but also in the lower digestivetract including the colon, comprising the steps of: (A) orallyadministering a preparation having a gelation index of 70% or more, saidpreparation comprising: (1) a drug, wherein the amount of said drug isnot more than 85% by weight based on the total preparation, (2) anadditive which has a solubility such that the volume of water requiredfor dissolving 1 gram of said additive is not more than 5 ml, whereinthe amount of said additive is from 5 to 80% by weight based on thetotal preparation, and (3) a hydrogel-forming polymer having a viscosityof not less than 1000 cps as measured at 1% concentration in water at25° C., wherein the amount of said hydrogel-forming polymer is from 10to 95% by weight based on the total preparation and not less than 70 mgper one preparation; and (B) absorbing water before the preparation isin the low-water lower digestive tract including the colon.
 23. A methodfor delivering a gel to the lower digestive tract including the colonfor drug-release, comprising the steps of: (A) orally administering apreparation having a gelation index of 70% or more, said preparationcomprising: (1) a drug, wherein the amount of said drug is not more than85% by weight based on the total preparation, (2) an additive which hasa solubility such that the volume of water required for dissolving 1gram of said additive is not more than 5 ml, wherein the amount of saidadditive is from 5 to 80% by weight based on the total preparation, and(3) a hydrogel-forming polymer having a viscosity of not less than 1000cps as measured at 1% concentration in water at 25° C., wherein theamount of said hydrogel-forming polymer is from 10 to 95% by weightbased on the total preparation and not less than 70 mg per onepreparation; (B) substantially complete gelling in the upper digestivetract including stomach and small intestine; and (C) releasing the drugnot only in the upper digestive tract including stomach and smallintestine but also in the lower digestive tract including the colon. 24.A method for maintaining a steady blood level of a drug, comprising thesteps of: (A) orally administering a preparation having a gelation indexof 70% or more, said preparation comprising: (1) a drug, wherein theamount of said drug is not more than 85% by weight based on the totalpreparation, (2) an additive which has a solubility such that the volumeof water required for dissolving 1 gram of said additive is not morethan 5 ml, wherein the amount of said additive is from 5 to 80% byweight based on the total preparation, and (3) a hydrogel-formingpolymer having a viscosity of not less than 1000 cps as measured at 1%concentration in water at 25° C., wherein the amount of saidhydrogel-forming polymer is from 10 to 95% by weight based on the totalpreparation and not less than 70 mg per one preparation; (B)substantially complete gelling in the upper digestive tract includingstomach and small intestine; and (C) releasing the drug not only in theupper digestive tract including stomach and small intestine but also inthe lower digestive tract including the colon.
 25. A method formaintaining a steady blood level of a drug, comprising the steps of: (A)solubilizing a drug to provide a preparation having a gelation index of70% or more, said solubilizing comprising combining the drug, in anamount not more than 85% by weight based on the total preparation, with(i) an additive which has a solubility such that the volume of waterrequired for dissolving 1 gram of said additive is not more than 5 ml,wherein the amount of said additive is from 5 to 80% by weight based onthe total preparation, and (ii) a hydrogel-forming polymer having aviscosity of not less than 1000 cps as measured at 1% concentration inwater at 25° C., wherein the amount of said hydrogel-forming polymer isfrom 10 to 95% by weight based on the total preparation and not lessthan 70 mg per one preparation; (B) orally administering the solubilizeddrug preparation of step (A); and (C) substantially complete gelling inthe upper digestive tract including stomach and small intestine;followed by drug-release in the lower digestive tract including thecolon.
 26. The method of claim 1, wherein the method comprises oraladministration to a human and the substantially complete gelation isabout 4 to 5 hours after administration.
 27. The method of claim 26,wherein the method comprises a portion of the preparation havingundergone gelation still remaining in the colon 6 hours afteradministration.
 28. The method of claim 27, wherein the method comprisesa portion of the preparation having undergone gelation still remainingin the colon 8 hours after administration.
 29. The method of claim 27,wherein the method comprises a portion of the preparation havingundergone gelation still remaining in the colon 12 hours afteradministration.
 30. A method for providing drug-release not only in theupper digestive tract including stomach and small intestine but also inthe lower digestive tract including the colon, comprising the steps of:(A) orally administering a preparation having a gelation index of 70% ormore, said preparation comprising: (1) a drug, wherein the amount ofsaid drug is not more than 85% by weight based on the total preparation,(2) an additive which has a solubility such that the volume of waterrequired for dissolving 1 gram of said additive is not more than 5 ml,wherein the amount of said additive is from 5 to 80% by weight based onthe total preparation, and (3) a hydrogel-forming polymer, wherein theamount of said hydrogel-forming polymer is from 10 to 95% by weightbased on the total preparation; (B) substantially complete gelling ofthe preparation in the upper digestive tract including stomach and smallintestine; (C) through travelling in gel-form to the lower digestivetract, releasing the drug not only in the upper digestive tractincluding stomach and small intestine but also in the lower digestivetract including the colon.